Diabetic peripheral neuropathy, the most common symptomatic chronic complication of diabetes and a major factor in diabetes-related morbidity, constitutes a major unsolved public health problem. Although thought to be conditioned by abnormalities in nerve metabolism related to hyperglycemia, diabetic neuropathy remains a disorder of unknown etiology for which no generally accepted treatment or prevention exists. The applicant has described a series of structural alterations at the node of Ranvier of myelinated fibers in insulin deficient humans and rats, that are linked to specific neurochemical defects related to hyperglycemia, account for a major component of impaired nerve conduction, and represent an early stage of the structural hallmarks of advanced clinical diabetic neuropathy. Early and reversible slowing of composite nerve conduction velocity and accompanying nodal swelling in the diabetic BB rat have been ascribed to intraaxonal Na accumulation, which in turn reflects impaired nerve (Na,K)-ATPase activity that has been traced to underlying defects in nerve myo-inositol and sorbitol metabolism related to hyperglycemia. Axo-glial dysjunction, a more advanced nodal lesion characterized by the loss of junctional complexes between terminal loops of myelin and the paranodal axolemma in diabetic rats and patients, produces a more permanent slowing of nerve conduction through secondary changes in nodal Na permeability and K-current leakage, and probably constitutes an early stage in the paranodal demyelination that characterizes advanced diabetic neuropathy. This application will explore the biochemical and morphomolecular basis and the functional consequence of axo-glial dysjunction in BB rat and organotypic and cell culture systems modeling diabetic peripheral nerve, using biochemical, molecular, immunohistochemical, ultrastructural and voltage clamp techniques. It is hypothesized that axo-glial junctions involve metabolically regulated cell and substrate adhesion molecules (CAM's and SAM'S, respectively) whose function and/or ultrastructural distribution is altered as a result of abnormal phosphoinositide signal transduction and/or non-enzymatic glycation in diabetic peripheral nerve, and that axo-glial dysjunction permits the loss of nodal Na channels through their lateral migration through the damaged axo-glial barrier into the internode. Elucidation of the mechanisms responsible for this functionally significant lesion of the strategic node of Ranvier in diabetic neuropathy may provide the basis for future therapies specifically directed at components of this pathological process.